Streptogramin derivatives, their preparation and compositions which contain them

ABSTRACT

Group A streptogramin derivatives of formula (I) and salts thereof:  
                 
 
     Group A streptogramin derivatives of formula (II) and salts thereof:  
                 
 
     and Group A streptogramin derivatives of formula (III) and salts thereof:  
                 
 
     as well as processes for preparing such streptogramins, and pharmaceutical compositions comprising such streptogramins, alone or combined with at least one group B streptogramin derivative.

[0001] Under the provisions of Section 119 of 35 U.S.C., Applicantshereby claim the benefit of French Application No. 00/16804, filed Dec.21, 2000, which is incorporated herein by reference. Applicants alsoclaim the benefit of U.S. Provisional Application No. 60/262,637, filedJan. 22, 2001, which is incorporated herein by reference.

[0002] The present invention relates to group A streptograminderivatives of formula (I):

[0003] which have advantageous antibacterial activity.

[0004] Among the known streptogramins, pristinamycin (RP 7293), anantibacterial agent of natural origin produced by Streptomycespristinaespiralis, was isolated for the first time in 1955. Thepristinamycin sold under the name Pyostacine® comprises mainlypristinamycin IIA combined with pristinamycin IA.

[0005] Another antibacterial agent of the streptogramin class,virginiamycin, was isolated from Streptomyces virginiae, ATCC 13161[Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin(Staphylomycine®) comprises mainly factor M₁ (VM1) combined with factorS (VS).

[0006] The inventors have now discovered that the group A streptograminderivatives of formula (I), wherein:

[0007] R₁ is chosen from cyano and ethynyl groups,

[0008] R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and

[0009] the bond

is a single bond (27R stereochemistry) or a double bond, haveadvantageous antibacterial activity, alone or when combined with atleast one group B streptogramin derivative.

[0010] The streptogramin derivatives of formula (I) may be prepared, forexample, by known, art-recognized methods. Such methods include reactinga 16-sulphonyloxy derivative of formula (II):

[0011] wherein:

[0012] R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup,

[0013] R₃ is a perfluoroalkyl group comprising from 1 to 10 carbonatoms, and

[0014] the bond

is a single bond (27R stereochemistry) or a double bond, with an alkalimetal cyanide, reducing the compound obtained from that reaction, andoptionally separating the 16R and 16S isomers obtained. Another methodincludes carbonylating an above-defined 16-sulphonyloxy derivative offormula (II) to form a lactone, reducing the lactone to a lactol,reacting the compound formed, i.e., the lactol, with dimethyldiazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate, andoptionally separating the 16R and 16S isomers obtained.

[0015] In one embodiment, the R₃ group is chosen from a trifluoromethylgroup and a nonafluorobutyl group.

[0016] In one embodiment, the alkali metal cyanide may be chosen frompotassium cyanide, sodium cyanide, and caesium cyanide.

[0017] The cyanation reaction can be carried out, for example, in thepresence of a palladium derivative, for example,tetrakis(triphenylphosphine)-palladium, and copper iodide. The processcan be performed, for example, in an organic solvent, such as, a nitrile(for example, acetonitrile), an ether (for example, tetrahydrofuran), anamide (for example, dimethylformamide or N-methylpyrrolidinone), at atemperature ranging, for example, from 20° C. to the reflux temperatureof the reaction mixture. The process can also be performed under aninert atmosphere, for example, argon or nitrogen.

[0018] The subsequent reduction may be carried out electrochemically,under an inert atmosphere, at a temperature of about 20° C., working ina buffer solution, such as, a solution degassed with argon, oftetraethylammonium tetrafluoroborate, tetraethylammonium acetate andacetic acid, under a potential difference of about −1.5 V (I=250 mA).Example 2 below gives a more detailed assessment of the operatingconditions which may be used.

[0019] Such a reaction can lead to a mixture of the 16R and 16S isomers,which may be separated according to known, art-recognized methods whichdo not affect the rest of the molecule. For example, the separation ofthe epimer forms may be carried out by chromatography, such as, HighPerformance Liquid Chromatography (HPLC) on normal or reverse phase,HPLC on a chiral or non-chiral phase, or by flash chromatography, bycrystallization, by centrifugal partition chromatography (CPC), or byany other appropriate separation technique available in the art.

[0020] The carbonylation reaction can be carried out under an atmosphereof carbon monoxide, such as, under one atmosphere, in the presence of apalladium derivative, for example,tetrakis(triphenylphosphine)-palladium, anhydrous lithium chloride and abase such as an alkali metal carbonate or alkaline-earth metalcarbonate, for example, potassium carbonate, sodium carbonate, orcaesium carbonate, in an inert organic solvent, such as an ether (forexample, tetrahydrofuran), a nitrile (for example, acetonitrile), anamide (for example, dimethylformamide or N-methylpyrrolidinone), at atemperature ranging, for example, from 0° C. to the reflux temperatureof the reaction mixture. In one embodiment of the process, the reactioncan be performed at about 20° C.

[0021] The carbonylation reaction leads to the formation of a lactone offormula (III):

[0022] wherein:

[0023] R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and

[0024] the bond

is a single bond (27R stereochemistry) or a double bond.

[0025] In one embodiment, the lactone can be reduced to a lactolsaturated at 16,17 and then reacted with dimethyl diazomethylphosphonateor dimethyl 1-diazo-2-oxopropylphosphonate to form an ethynylderivative.

[0026] The reduction of the lactone to a lactol may be carried out inthe presence of a hydride such as, for example, lithium or potassiumtri-sec-butylborohydride (L or K Selectride), in an inert organicsolvent, such as an ether (for example, tetrahydrofuran) at atemperature ranging, for example, from −60° C. to 20° C., such as, atabout −20° C., and under an inert atmosphere (for example, nitrogen orargon).

[0027] The reaction of dimethyl diazomethylphosphonate or dimethyl1-diazo-2-oxopropylphosphonate can be carried out by applying themethods described by H. J. Bestmann et al., Synlett, 521 (1996) or by K.C. Nicolaou, Tetrahedron, 50(39), 11391 (1994), the relevant methodsthereof are incorporated herein by reference. Such methods include aprocess performed in an inert solvent, such as, an ether (for example,tetrahydrofuran) or an alcohol (for example, methanol), at a temperatureranging, for example, from −78° C. to 40° C., such as, at about 20° C.The process can be performed under an inert atmosphere (for example,argon or nitrogen).

[0028] The reaction can also lead to a mixture of the 16R and 16Sisomers, which may be separated according to known, art-recognizedmethods which do not affect the rest of the molecule. Such methods can,for example, include chromatography, such as, High Performance LiquidChromatography (HPLC) on normal or reverse phase, HPLC on a chiral ornon-chiral phase, and flash chromatography. Crystallization, centrifugalpartition chromatography (CPC), or any other appropriate separationtechnique available in the art can also be used.

[0029] Streptogramin derivatives of formula (II) may be obtained, forexample, by reacting a fluoride or anhydride, wherein the fluoride oranhydride comprises a perfluoroalkyl group comprising 1 to 10 carbonatoms, with a streptogramin derivative of formula (IV):

[0030] wherein:

[0031] R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and

[0032] the bond

is a single bond (27R stereochemistry) or a double bond,

[0033] in the presence of a base, such as, a tertiary amine (forexample, diisopropylethylamine or triethylamine), in an inert organicsolvent, such as, a chlorinated solvent (for example, dichloromethane),an ether (for example, tetrahydrofuran) or an amide (for example,dimethylformamide) at a temperature ranging from −78° C. to 20° C., suchas, at about −70° C., and under an inert atmosphere (for example, argonor nitrogen).

[0034] In one embodiment, the sulphonic anhydride (for example, triflicanhydride) or the sulphonyl fluoride (for example,perfluoro-1-butanesulphonyl fluoride) corresponding to the selected R₃group can be reacted.

[0035] The pristinamycin derivatives of formula (IV) correspond,respectively, to pristinamycin IIA (PIIA), pristinamycin IIB (PIIB),pristinamycin IIC (PIIC), pristinamycin IID (PIID), pristinamycin IIF(PIIF) and pristinamycin IIG (PIIG), which are known components ofnatural pristin amycin. The components PIIF and PIIG have been disclosedin European patent application no. EP-A-0 614 910. Pristinamycin IIC(PIIC) and pristinamycin IID (PIID) may be obtained as described by J.C. Barrière et al., Expert. Opin. Invest. Drugs, 3(2), 115-31 (1994).

[0036] The preparation and separation of natural group A streptogramincomponents, such as, streptogramins of formula (IV), can be carried outby fermentation and isolation of the constituents from the fermentationmust according to or by analogy with the method described by J.Preud'homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968), or inEuropean patent application no. EP-A-0 614 910. Additionally, thepreparation of natural group A components may be carried out, forexample, by specific fermentation, as disclosed in French patentapplication no. FR-A-2 689 518.

[0037] The group A streptogramin derivatives of formulae (II) and (III)are novel products that are useful for preparing streptograminderivatives according to the invention.

[0038] The streptogramin derivatives of formula (I) may be purified,when appropriate, by physical methods, such as, crystallization,chromatography, and CPC.

[0039] The streptogramin derivatives according to the present inventionhave superior antibacterial properties and synergistic properties withrespect to the antibacterial activity of the group B streptograminderivatives. They are notably advantageous on account of their powerfulactivity, alone or in combination.

[0040] When at least one group A streptogramin derivative of theinvention is combined with at least one group B streptogramin componentor derivative, this component or derivative may be chosen, depending onwhether it is desired to obtain a form for oral or parenteraladministration, from the following natural components: pristinamycin IA,pristinamycin IB, pristinamycin IC, pristinamycin ID, pristinamycin IE,pristinamycin IF, pristinamycin IG, virginiamycin S1, S3 or S4,vernamycin B or C, etamycin or from semisynthetic derivatives asdisclosed in U.S. Pat. Nos. or European patent application nos. U.S.Pat. No. 4,618,599, U.S. Pat. No. 4,798,827, U.S. Pat. No. 5,326,782,EP-A-0 772 630 and EP-A-0 770 132.

[0041] Representative group B streptogramin components and derivativesmay include, for example, (I) streptogramin derivatives of formula (A),and salts thereof:

[0042] wherein:

[0043] (1) Rb, Rc, Re, and Rf are each a hydrogen atom;

[0044] Rd is chosen-from a hydrogen atom and a dimethylamino group; and

[0045] Ra is chosen from:

[0046] (A) —CH₂R′a groups, wherein R′a is chosen from:

[0047] (i) a pyrrolidinyl-3-thio group,

[0048] (ii) a piperidyl-3-thio group,

[0049] (iii) a piperidyl-4-thio group,

[0050] wherein groups (i)-(iii) may be unsubstituted or substituted withat least one group chosen from alkyl groups, and

[0051] (iv) alkylthio groups which are substituted with 1 or 2 groupschosen from:

[0052] (a) a hydroxysulfonyl group,

[0053] (b) alkylamino groups,

[0054] (c) dialkylamino groups, which may be unsubstituted orsubstituted with at least one group chosen from a mercapto group ordialkylamino groups,

[0055] (d) a piperazine ring which may be substituted or unsubstituted,a morpholino group, a thiomorpholino group, a piperidino group, a1-pyrrolidinyl group, a 2-piperidyl group, a 3-piperidyl group, a4-piperidyl group, a 2-pyrrolidinyl group, and a 3-pyrrolidinyl group,each of which may be unsubstituted or substituted with at least onegroup chosen from alkyl groups, and

[0056] (B) ═CHR'a groups, wherein R'a is chosen from:

[0057] (i) a pyrrolidinyl-3-amino group,

[0058] (ii) a piperidyl-3-amino group and a piperidyl-4-amino group,

[0059] (iii) a pyrrolidinyl-3-oxy group,

[0060] (iv) a piperidyl-3-oxy group and a piperidyl-4-oxy group,

[0061] (v) a pyrrolidinyl-3-thio group,

[0062] (vi) a piperidyl-3-thio group and a piperidyl-4-thio group,

[0063] wherein groups (i)-(vi) may be unsubstituted or substituted withat least one group chosen from alkyl groups,

[0064] (vii) alkylamino groups,

[0065] (viii) alkyloxy groups, and

[0066] (ix) alkylthio groups,

[0067] wherein groups (vii), (viii), and (ix) are substituted with 1 or2 groups chosen from:

[0068] (a) a hydroxysulfonyl group,

[0069] (b) alkylamino groups,

[0070] (c) dialkylamino groups unsubstituted or substituted with atleast one group chosen from dialkylamino groups,

[0071] (d) trialkylammonio groups,

[0072] (e) a 4-imidazolyl group, and a 5-imidazolyl group, each of whichmay be unsubstituted or substituted with at least one group chosen fromalkyl groups,

[0073] (f) a piperazine ring which may be substituted or unsubstituted,a morpholino group, a thiomorpholino group, a piperidino group, a1-pyrrolidinyl group, a 2-piperidyl group, a 3-piperidyl group, a4-piperidyl group, a 2-pyrrolidinyl group, and a 3-pyrrolidinyl group,each of unsubstituted or substituted with at least one group chosen fromalkyl groups,

[0074] (C) a quinuclidinyl-3-thiomethyl group, and

[0075] (D) a quinuclidinyl-4-thiomethyl group; or

[0076] (2) Ra is a hydrogen atom, and

[0077] (a) Rb, Re, and Rf are each a hydrogen atom, and

[0078] Rd is chosen from a —NHCH₃ group and a —N(CH₃)₂ group, and Rc ischosen from a chlorine atom and a bromine atom, or, when Rd is a—N(CH₃)₂ group, Rc is chosen from (C₃-C₅) alkenyl groups, or

[0079] (b) Rb, Rd, Re, and Rf are each a hydrogen atom, and

[0080] Rc is chosen from halogen atoms, aminomonoalkyl groups,aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group,thioalkyl groups, (C₁-C₃) alkyl groups, and trihalomethyl groups, or

[0081] (c) Rb, Rc, Re, and Rf are each a hydrogen atom, and

[0082] Rd is chosen from halogen atoms, an ethylamino group, adiethylamino group, a methylethylamino group, alkyloxy groups, atrifluoromethyloxy group, thioalkyl groups, (C₁-C₆) alkyl groups, arylgroups, and trihalomethyl groups, or

[0083] (d) Rb, Re, and Rf are each a hydrogen atom,

[0084] Rc is chosen from ha!ogen atoms, aminomonoalkyl groups,aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group,thioalkyl groups, and (C₁-C₃) alkyl groups, and

[0085] Rd is chosen from halogen atoms, an amino group, aminomonoalkylgroups, aminodialkyl groups, alkyloxy groups, a trifluoromethyloxygroup, thioalkyl groups, (C₁-C₆) alkyl groups, and trihalomethyl groups,or

[0086] (e) Rc, Re, and Rf are each a hydrogen atom, and

[0087] Rb and Rd are each a methyl group,

[0088] and further, for example, (11) semisynthetic group Bstreptogramin derivatives of formula (B), and salts thereof:

[0089] wherein:

[0090] (A) Y is chosen from (i) a nitrogen atom and (ii) ═CR₃— groups,and

[0091] (1) when Y is chosen from ═CR₃— groups, R₁ is chosen from

[0092] (a₁) a hydrogen atom, C₁-C₈ alkyl groups, and C₂-C₈ alkenylgroups,

[0093] (b₁) C₃-C₈ cycloalkyl groups, and saturated and unsaturated 3- to8-membered heterocyclyl groups,

[0094] (c₁) an unsubstituted phenyl group,

[0095] (d₁) a phenyl group substituted with at least one substituentchosen from halogen atoms, a hydroxyl group, alkyl groups, alkyloxygroups, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups,an amino group, alkylamino groups, and dialkylamino groups, and

[0096] (e₁) groups +NR′R″, wherein:

[0097] R′ and R″, which are identical or different, are each chosen froma hydrogen atom, and C₁-C₃ alkyl groups, or

[0098] R′ and R″, form, together with the nitrogen atom to which theyare attached, a 3- to 8-membered heterocyclyl group, wherein one of themembers, in addition to the nitrogen atom, may be a heteroatom chosenfrom an oxygen atom, a sulphur atom, and a nitrogen atom, and whereinthe heterocyclyl group is unsubstituted or substituted with a groupchosen from alkyl groups, C₂-C₈ alkenyl groups, C₃-C₆ cycloalkyl groups,saturated and unsaturated 4- to 6-membered heterocyclyl groups, a benzylgroup, an unsubstituted phenyl group, and a substituted phenyl group, asdefined above in (d₁),

[0099] (f₁) halomethyl groups, a hydroxymethyl group, and alkyloxymethylgroups,

[0100] (g₁) alkylthiomethyl groups, wherein the alkyl portion isunsubstituted or substituted with an —NR′R″ group, and wherein R′ and R″are as defined above in (e₁),

[0101] (h₁) alkylsulphinylmethyl groups, alkylsulphonylmethyl groups, anacyloxymethyl group, a benzoyloxymethyl group, a cyclopropylaminomethylgroup, and —(CH₂)_(n)NR′R″ groups, wherein n is chosen from integersranging from 1 to 4, and wherein R′ and R″ are as defined above in (e₁),and

[0102] (i₁) when R₃ is a hydrogen atom, R₁ is additionally chosen from aformyl group, a carboxyl group, alkyloxycarbonyl groups, and

[0103] CONR′R″ groups, wherein R′ and R″ are defined as above in (e₁),and

[0104] (2) when Y is a nitrogen atom, R₁ is chosen from

[0105] (a₂) options (a₁), (b₁), (c₁), (d₁), and (e₁) as defined above,and

[0106] (b₂) XR^(o) groups, wherein X is chosen from an oxygen atom, asulphur atom, a sulphinyl group, a sulphonyl group, and an —NH— group,and wherein R^(o) is chosen from (i) (C₁ to C₈) alkyl groups, (i) (C₃ toC₆) cycloalkyl groups, (iii) saturated and unsaturated 3- to 8-memberedheterocyclyl groups, (iv) 3- to 8-membered heterocyclylmethyl groups inwhich the heterocyclyl portion is attached to the methyl group by acarbon atom, (v) an unsubstituted phenyl group, (v₁) phenyl groupssubstituted with at least one group chosen from halogen atoms, ahydroxyl group, alkyl groups, alkyloxy groups, alkylthio groups,alkylsulfinyl groups, alkylsulfonyl groups, an amino group, alkylaminogroups, and dialkylamino groups, (vi) —(CH₂)_(n)NR′R″ groups, wherein R′and R″ are as defined above in (e₁), and wherein n is chosen fromintegers ranging from 2 to 4, and (viii) if X is an NH group, R^(o) mayalso be a hydrogen atom;

[0107] (B) R₂ is chosen from a hydrogen atom and C₁-C₃ alkyl groups,

[0108] (C) R₃ is chosen from a hydrogen atom, alkyl groups, a carboxylgroup, alkyloxycarbonyl groups, and carbamoyl groups of formula—CO—NR′R″, wherein R′ and R″ are defined as above in (e₁),

[0109] (D) Ra is chosen from a methyl group and an ethyl group, and

[0110] (E) Rb, Rc, and Rd are defined as follows:

[0111] (1) Rb and Rc are each a hydrogen atom, and

[0112] Rd is chosen from a hydrogen atom, a methylamino group, and adimethylamino group, or

[0113] (2) Rb is a hydrogen atom,

[0114] Rc is chosen from a hydrogen atom, a chlorine atom, a bromineatom, and C₃-C₅ alkenyl groups, and

[0115] Rd is chosen from —N(CH₃)R′″ groups, wherein

[0116] R′″ is chosen from

[0117] (a) alkyl groups,

[0118] (b) C₂-C₄ hydroxyalkyl groups,

[0119] (c) C₂-C₈ alkenyl groups, wherein the C₂-C₈ alkenyl groups areunsubstituted or substituted with (₁) an unsubstituted phenyl group,(ii) a cycloalkyl(C₃-C₆)methyl group, (iii) an unsubstituted benzylgroup, (iv) a benzyl group substituted with at least one substituentchosen from halogen atoms, a hydroxyl group, alkyl groups, alkyloxygroups, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups,an amino group, alkylamino groups, and dialkylamino groups, or (v)heterocyclylmethyl groups and heterocyclylethyl groups, wherein theheterocyclyl portions of the heterocyclylmethyl groups and theheterocyclylethyl groups are chosen from saturated and unsaturated 5- to6-membered heterocyclyl groups comprising from 1 to 2 heteroatoms chosenfrom a sulphur atom, an oxygen atom, and a nitrogen atom, and whereinthe heterocyclyl groups may be unsubstituted or substituted with a groupchosen from alkyl groups, C₂-C₈ alkenyl groups, C₃-C₆ cycloalkyl groups,saturated and unsaturated 4- to 6-membered heterocyclyl groups, anunsubstituted phenyl group, a benzyl group, or a substituted phenylgroup as defined above in (d₁),

[0120] (d) a cyanomethyl group,

[0121] (e) —CH₂CORe groups, wherein Re is chosen from (i) —OR′e groups,wherein R′e is chosen from a hydrogen atom, C₁-C₆ alkyl groups, C₂-C₆alkenyl groups, a benzyl group, and heterocyclylmethyl groups, whereinthe heterocyclyl portion is chosen from 5- to 6-membered heterocyclylgroups comprising from 1 to 2 heteroatoms chosen from a sulphur atom, anoxygen atom, and a nitrogen atom, (ii) alkylamino groups,alkylmethylamino groups, heterocyclylamino groups andheterocyclylmethylamino groups, wherein the heterocyclyl portion of theheterocyclylamino groups and the heterocyclylmethylamino groups ischosen from 5- to 6-membered saturated heterocyclyl groups comprisingfrom 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, anda nitrogen atom, and wherein the heterocyclyl groups may beunsubstituted or substituted with a group chosen from alkyl groups, abenzyl group, and alkyloxycarbonyl groups, or

[0122] (3) Rb is a hydrogen atom,

[0123] Rd is chosen from an —NHCH₃ group and an —N(CH₃)₂ group, and

[0124] Rc is chosen from a chlorine atom, and a bromine atom, and whenRd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenyl groups, or

[0125] (4) Rb and Rd are each a hydrogen atom, and

[0126] Rc is chosen from halogen atoms, alkylamino groups, dialkylaminogroups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups,C₁-C₆ alkyl groups, and trihalomethyl groups, or

[0127] (5) Rb and Rc are each a hydrogen atom, and

[0128] Rd is chosen from halogen atoms, an ethylamino group, adiethylamino group, a methylethylamino group, alkyloxy groups, atrifluoromethoxy group, alkylthio groups, alkylsulphinyl groups,alkylsulphonyl groups, C₁-C₆ alkyl groups, a phenyl group, andtrihalomethyl groups, or

[0129] (6) Rb is a hydrogen atom, and

[0130] Rc is chosen from halogen atoms, alkylamino groups, dialkylaminogroups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, andC₁-C₃ alkyl groups, and

[0131] Rd is chosen from halogen atoms, an amino group, alkylaminogroups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group,thioalkyl groups, C₁-C₆ alkyl groups, and trihalomethyl groups, or

[0132] (7) Rc is a hydrogen atom, and

[0133] Rb and Rd are each a methyl group, and

[0134] even further, for example, (III) semisynthetic group Bderivatives of formula (C), and salts thereof, when salts exists:

[0135] wherein:

[0136] (A) R is chosen from

[0137] (1) —NR₁R₂ groups, wherein R₁ and R₂, which may be identical ordifferent, are each chosen from

[0138] (i) a hydrogen atom,

[0139] (ii) (C₁-C₈) alkyl groups,

[0140] (iii) (C₁-C₈) alkyl groups substituted with a hydroxyl group,

[0141] (iv) (C₃-C₈) alkenyl groups,

[0142] (v) (C₃-C₈) cycloalkyl groups,

[0143] (vi) (C₁-C₈) alkyloxy groups,

[0144] (vii) dialkylamino groups,

[0145] (viii) phenylalkyl groups,

[0146] (ix) phenylalkyl groups substituted with at least one groupchosen from halogen atoms, alkyl groups, hydroxyalkyl groups, alkyloxygroups, and dialkylamino groups, and

[0147] (x) 3- to 8-membered saturated and unsaturated heterocyclylalkylgroups comprising at least one hetero atom chosen from nitrogen, oxygen,and sulphur, or

[0148] (xi) R₁ and R₂ form, together with the nitrogen atom to whichthey are attached, a saturated, partially saturated or unsaturated mono-or polycyclic 3- to 12-membered heterocycle group, wherein one of themembers, in addition to the nitrogen atom, may be an atom chosen fromoxygen, sulphur, and nitrogen, and wherein the heterocyclyl group isunsubstituted or substituted with at least one group chosen from ahydroxyl group, alkyl groups, an unsubstituted phenyl group, a phenylgroup substituted with a halogen atom, phenylalkyl groups,phenyl(C₂-C₄)alkenyl groups, hydroxyalkyl groups, acyl groups,alkyloxycarbonyl groups, heterocyclyl groups and heterocyclylcarbonylgroups, wherein the heterocyclyl portion is saturated or unsaturated (4-to 6-membered) and comprises at least one hetero atom chosen fromnitrogen, sulphur, and oxygen, and

[0149] (2) —SR₃ groups, wherein R₃ is chosen from

[0150] (i) (C₁-C₈) alkyl groups and(C₃-C₈) cycloalkyl groups substitutedwith —NR₁R₂, wherein R₁ and R₂, which may be identical or different, areeach chosen from a hydrogen atom and alkyl groups, or form, togetherwith the nitrogen atom to which they are attached, a heterocycle asdefined in (xi) above, and

[0151] (ii) 3- to 7-membered saturated and unsaturated heterocyclyl andheterocyclylmethyl groups, wherein one of the members, in addition tothe nitrogen atom, may be a heteroatom chosen from oxygen, sulphur, andnitrogen, and wherein the heterocyclyl portion is unsubstituted orsubstituted with at least one group chosen from alkyl groups,

[0152] (B)

[0153] is a residue of an unsaturated ring which is not substituted inthe 5γ position

[0154] or the residue of a saturated ring which is substituted in the 5γposition with a fluorine atom

[0155] (C) Ra is chosen from a methyl group and an ethyl group, and

[0156] (D) Rb, Rc and Rd are defined below:

[0157] 1) Rb and Rc are each a hydrogen atom, and

[0158] Rd is chosen from a hydrogen atom, a methylamino group, and adimethylamino group, or

[0159] 2) Rb is a hydrogen atom,

[0160] Rc is chosen from a hydrogen atom, a chlorine atom, a bromineatom, and a (C₃ to C₅) alkenyl group, and

[0161] Rd is —N(CH₃)—R′″, wherein R′″ is chosen from:

[0162] (1) alkyl groups, (2) (C₂ to C₄) hydroxyalkyl groups, (3) (C₂ toC₈) alkenyl groups, (4) phenylalkenyl groups, (5) cycloalkyl(C₃ toC₆)methyl groups, (6) an unsubstituted benzyl group, (7) a substitutedbenzyl group, (8) heterocyclylmethyl groups and heterocyclylethylgroups, (9) a —CH₂CN group, (10) a —CH₂COOH group, and (11) —CORe groupsand —CH₂CORe groups for which either:

[0163] (a) Re is —OR′e, wherein R′e is chosen from a hydrogen atom,C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, a benzyl group, andheterocyclylmethyl groups, wherein the heterocyclyl portion is chosenfrom 5- to 6- membered heterocyclyl groups comprising from 1 to 2heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogenatom, or

[0164] (b) Re is chosen from alkylamino groups, alkylmethylamino groups,heterocyclylamino groups, and heterocyclylmethylamino groups, or

[0165] 3) Rb is a hydrogen atom,

[0166] Rd is chosen from an —NHCH₃ group and an —N(CH₃)₂ group, and

[0167] Rc is chosen from a chlorine atom, and a bromine atom, and whenRd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenyl groups, or

[0168] 4) Rb and Rd are each a hydrogen atom, and

[0169] Rc is chosen from halogen atoms, alkylamino groups, dialkylaminogroups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups,(C₁-C₆) alkyl groups, and trihalomethyl groups, or

[0170] 5) Rb and Rc are each a hydrogen atom, and

[0171] Rd is chosen from halogen atoms, an ethylamino group, adiethylamino group, a methylethylamino group, alkyloxy groups, atrifluoromethoxy group, alkylthio groups, alkylsulphinyl groups,alkylsulphonyl groups, (C₁-C₆) alkyl groups, a phenyl group, andtrihalomethyl groups, or

[0172] 6) Rb is a hydrogen atom,

[0173] Rc is chosen from halogen atoms, alkylamino groups, dialkylaminogroups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups,(C₁-C₃) alkyl groups, and

[0174] Rd is chosen from halogen atoms, an amino group, alkylaminogroups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group,thioalkyl groups, (C₁-C₆) alkyl groups, and trihalomethyl groups, or

[0175] 7) Rc is a hydrogen atom, and

[0176] Rb and Rd are each a methyl group.

[0177] It is understood that the combinations formed from thederivatives according to the invention and from group B streptograminsalso fall within the context of the present invention.

[0178] The group B streptogramin derivatives of formula (B) may beprepared, for example, according to the methods disclosed inInternational patent application no. PCT/FR 99/00409. The group Bstreptogramin derivatives of formula (C) may be prepared, for example,according to the methods disclosed in International patent applicationno. PCT/FR 00/02146.

[0179] In vitro on Staphylococcus aureus IP8203, the streptograminderivatives according to the invention have been shown to be active atconcentrations of between 0.015 and 32 μg/ml, alone or combined with agroup B derivative such as pristinamycin IB. In vivo, the streptograminderivatives according to the invention synergized the antimicrobialactivity of pristinamycin I_(B) or of semisynthetic derivatives offormula (C) on experimental infections of mice with Staphylococcusaureus IP8203 at doses ranging, for example, from 72 to 150 mg/kg orally(DC₅₀).

[0180] The compounds according to the invention are advantageous onaccount of their low toxicity. None of the compounds of the inventionhave shown any toxicity at doses of 150 mg/kg on Staphylococcus aureusIP8203, when administered twice a day subcutaneously or orally in mice.

[0181] Representative group A streptogramin derivatives of formula (I),which may be used according to the invention, for example, includestreptogramin derivatives of formula (I), wherein:

[0182] R₁ is chosen from a cyano group and an ethynyl group,

[0183] R₂ is a methyl group, and

[0184] the bond

is a single bond (27R stereochemistry) or a double bond, areadvantageous. The compounds described below in the Examples areexemplary of such derivatives.

[0185] Representative group A streptogramin derivatives of formula (I),which may be used according to the invention, for example, include thecompounds mentioned below in the examples, and the following compounds:

[0186] (16R)-16-deoxo-16-ethynylpristinamycin II_(A)

[0187] (16S)-16-deoxo-16-ethynylpristinamycin II_(A)

[0188] (16R)-16-cyano-16-deoxopristinamycin II_(A)

[0189] (16S)-16-cyano-16-deoxopristinamycin II_(A)

[0190] The examples which follow, given without any implied limitation,illustrate the present invention.

[0191] In the examples which follow, the 16-deoxopristinamycin IIA (orIIB) nomenclature indicates the replacement of the ketone function inposition 16 with 2 hydrogen atoms. As the chromatography proceeded, allthe fractions were analyzed by thin layer chromatography (TLC) on Merck60F254 silica plates. The fractions corresponding to the same spot onTLC were combined and then concentrated to dryness, under reducedpressure (30° C.; 2.7 kPa). The residues thus obtained were analyzed byknown, art-recognized spectroscopic techniques (such as, NMR, IR, andMS), allowing the expected product to be identified.

EXAMPLE 1

[0192] 16-Deoxo-16-ethynylpristinamycin II_(B):(mixture of the 16R and16S isomers in 70/30 proportions)

[0193] 0.415 g of potassium carbonate and 0.35 g of dimethyl1-diazo-2-oxopropylphosphonate were added, at 20° C. under an argonatmosphere, to 0.8 g of (16R)-16-deoxo-14,16-butyrolactolpristinamycinII_(B) dissolved in 40 cm³ of methanol. After stirring overnight, thereaction mixture was diluted with 100 cm³ of dichloromethane and thenwashed with 70 cm³ of saturated aqueous sodium bicarbonate solution. Theorganic phase was separated out after settling had taken place,concentrated under reduced pressure (2.7 kPa) to 30 cm³ and the residuewas diluted by adding 70 cm³ of dichloromethane. The solution obtainedwas washed with 40 cm³ of water. The organic phase was separated outafter settling had taken place, dried over magnesium sulphate, filteredand then concentrated to dryness under reduced pressure (2.7 kPa) togive 0.8 g of a pale yellow foam, which was purified by flashchromatography on silica [eluent:dichloromethane/acetonitrile/methanol(95/2.5/2.5 by volume)]. After concentrating the fractions containingthe expected product, a solid was obtained, which was stirred in 15 cm³of diisopropyl ether and then filtered off and dried under reducedpressure (2.7 kPa) to give 0.27 g of 16-deoxo-16-ethynylpristinamycinII_(B) (mixture of the 16R and 16S isomers in 70/30 proportions), in theform of a white solid that melted at about 128° C. with decomposition.

[0194]¹H NMR spectrum (300 MHz, CDCl₃, δ in ppm). We observed a mixtureof the (16R) and (16S) isomers in 70/30 proportions.

[0195] 0.96 (d, J=6.5 Hz:3H); 1.00 (mt:3H); 1.09 (mt:3H); from 1.45 to1.60 and 1.70 to 2.30 (2 series of mt:7H); 1.82 and 1.87 (2s:3H intotal); 2.14 and 2.24 (2d, J=2 Hz: 1H in total); 2.75 (mt:1H); from 2.75to 2.90 and from 2.95 to 3.15 (2 series of mt:3H in total); from 3.35 to3.65 (mt:1 H in total); from 3.75 to 3.95 and 4.08 (2 series of mt: 2Hin total); 4.50 (mt:1 H); from 4.70 to 4.90 (mt:3H); 5.35 and 5.52 (2broad d, J=9 Hz:1 H in total); from 5.60 to 5.85 (mt:1 H); 5.83 (dd,J=16.5 and 1.5 Hz:1H); 5.90 and 5.99 (2 mts:1H in total); 6.18 and 6.20(2d, J=16 Hz:1H in total); 6.48 and 6.51 (2 dd, J=16.5 and 5 Hz:1H intotal); 8.09 and 8.11 (2 s:1H in total).

[0196] The 16R and 16S isomers were separated by high performance liquidchromatography on a stationary silica phase (preparative column:80×350mm; stationary phase:Hypersil 8 μm silica; mobile phase:CH₂Cl₂ 46%+50%heptane+2% MeOH+2% CH₃CN; flow rate:100 ml/min; detection:UV 265 nm). Asolution of 1.1 g of 16-deoxo-16-ethynylpristinamycin II_(B) (mixture ofthe 16R and 16S isomers in 70/30 proportions) in 100 cm³ ofdichloromethane was injected onto the preparative column. The entireoperation was repeated a second time on an identical solution. Afterconcentrating the fractions containing the A isomer, 0.99 g of the Aisomer of 16-deoxo-16-ethynylpristinamycin II_(B) was obtained in theform of a white powder.

[0197] A isomer:¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.97 (d,J=6.5 Hz:3H); 1.01 (d, J=6.5 Hz:3H); 1.10 (d, J=6.5 Hz:3H); 1.56(mt:1H); from 1.75 to 2.05 (mt:5H); 1.87 (s:3H); from 2.05 to 2.15(mt:1H); 2.15 (d, J=2 Hz:1H); 2.77 (mt:1H); 2.81 (dd, J=16 and 8 Hz:1H);3.04 (mt:1H); 3.10 (dd, J=16 and 6.5 Hz:1H); 3.54 (mt:1H); 3.88 (mt:1H);4.09 (mt:1H); 4.52 (mt:1H); from 4.75 to 4.85 (mt:3H); 5.36 (broad d,J=9 Hz:1H); 5.76 (ddd, J=16−8 and 4 Hz:1H); 5.83 (broad d, J=16.5Hz:1H); 6.02 (mt:1H); 6.21 (d, J=16 Hz:1H); 6.52 (dd, J=16.5 and 5 Hz:1H); 8.10 (s:1H).

[0198] After concentrating the fractions containing the B isomer, 0.5 gof the B isomer of 16-deoxo-16-ethynylpristinamycin II_(B) was obtainedin the form of a white powder.

[0199] B isomer:¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.97 (d,J=6.5 Hz:3H); 1.01 (d, J=6.5 Hz:3H); 1.09 (d, J=6.5 Hz:3H); from 1.70 to2.05 (mt: 5H); 1.83 (s:3H); from 2.05 to 2.20 (mt:2H); 2.25 (d, J=2Hz:1H); 2.76 (mt:1H); from 3.00 to 3.15 mt:3H); 3.40 (mt:1H); from 3.80to 4.00 (mt:2H); 4.51 (mt:1H); from 4.70 to 4.85 (mt:2H); 4.87 (mt:1H);5.54 (broad d, J=9 Hz:1H); 5.67 (mt:1H); 5.79 (broad d, J=16.5 Hz:1H);5.91 (mt:1H); 6.19 (d, J=16 Hz:1H); 6.49 (dd, J=16.5 and 5 Hz:1H); 8.12(s:1H).

[0200] Dimethyl 1-diazo-2-oxopropylphosphonate was prepared according toCallant et al., Synth. Comm. (1984) p.155.

[0201] (16R)-16-Deoxo-14,16-butyrolactolpristinamycin II_(B) wasobtained in the following manner:

[0202] 15.5 cm³ of L-Selectride® were added slowly, at −20° C. under anargon atmosphere, to 4.18 g of16,17-dehydro-16-deoxo-14,16-butyrolactonepristinamycin II_(B) suspendedin 84 cm³ of tetrahydrofuran. After stirring for 1 hour, 1.7 cm³ ofacetic acid were added, followed by addition of 450 cm³ of water. Thereaction mixture was extracted 3 times with 120 cm³ of ethyl acetate.The organic phases were combined, washed with 150 cm³ of saturatedaqueous sodium chloride solution, dried over magnesium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) and gave, after stirring in 150 cm³ of diethyl ether, a white foam.After purification by flash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (96/2/2 by volume)] andconcentration of the fractions containing the expected products, 1.8 gof (16R)-16-deoxo-14,16-butyrolactolpristinamycin II_(B) were obtainedin the form of a white solid.

[0203]¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.99 (d, J=6.5 Hz:3H);1.07 (d, J=6.5 Hz:3H); 1.10 (d, J=6.5 Hz:3H); from 1.65 to 2.25 (mt:6H);1.73 (s: 3H); 2.47 (mt:1H); 2.66 (mt:1H); 2.79 (mt:1H); 2.84 (dd, J=16and 4 Hz:1H); 301 (dd, J=16 and 7 Hz:1H); 3.56 (mt:1H); 4.03 (mt:1H);4.10 (mt:1H); 4.56 (mt:1H); 4.70 (dd, J=8 and 3 Hz:1H); 4.74 (dd, J=10and 1.5 Hz:1H); 5.08 (mt:1H; from 5.35 to 5.45 (mt:2H); 5.74 (ddd,J=16−5 and 4 Hz:1H); 5.83 (dd, J=16.5 and 1.5 Hz :1H); 6.10 (mt:1H);6.19 (d, J=16 Hz:1H); 6.52 (dd, J=16.5 and 5 Hz:1H); 8.17 (s: 1H).

[0204] 16,17-Dehydro-16-deoxo-14,16-butyrolactonepristinamycin II_(B)was prepared in the following manner:

[0205] 1.47 g of tetrakis(triphenylphosphine)palladium, 3.37 g oflithium chloride and 8.8 g of potassium carbonate were added, at 20° C.under an argon atmosphere, to 21 g of16,17-dehydro-16-trifluoromethanesulphonyloxy-pristinamycin II_(B)dissolved in 250 cm³ of tetrahydrofuran. Carbon monoxide was bubbledinto the reaction mixture for 27 hours, after which 4.4 g of potassiumcarbonate were added and the bubbling of carbon monoxide into thereaction mixture was continued for 68 hours. The reaction mixture wasfiltered through Celite®, diluted with 250 cm³ of dichloromethane andstirred with 200 cm³ of saturated aqueous sodium chloride solution.After filtration through Celite®, the organic phase was washed twicewith 200 cm³ of saturated aqueous sodium chloride solution, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) to give 13.5 g of16,17-dehydro-16-deoxo-14,16-butyrolactonepristinamycin II_(B) in theform of a yellow solid.

[0206]¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.96 (d, J=6.5 Hz:3H);1.01 (d, J=6.5 Hz:3H); 1.12 (d, J=6.5 Hz:3H); from 1.65 to 2.05 (mt:4H);1.77 (s: 3H); 2.17 (mt:1H); 2.76 (mt:1H); from 3.30 to 3.45 (mt:2H);3.99 (broad d, J=17 Hz: 1H); from 4.00 to 4.15 (mt:2H); 4.46 (mt:1H);4.81 (dd, J=10 and 1.5 Hz:1H); 4.93 (dd, J=8 and 3 Hz:1H); from 5.50 to5.65 (mt:2H); from 5.65 to 5.80 (mt:2H); 5.81 (dd, J=16.5 and 1.5Hz:1H); 6.11 (d, J=16 Hz:1H); 6.51 (dd, J=16.5 and 5 Hz; 1H); 7.23(mt:1H); 8.42 (s:1H).

[0207] 16,17-Dehydro-16-trifluoromethanesulphonyloxypristinamycin II_(B)was prepared in the following manner:

[0208] 5 cm³ of diisopropylethylamine and 2.3 cm³ of triflic anhydridewere added, at −70° C. under an argon atmosphere, to 5 g ofpristinamycin II_(B) dissolved in 210 cm³ of dichloromethane. Afterstirring for 2.5 hours at −74° C., the reaction mixture was poured into200 cm³ of saturated aqueous sodium bicarbonate solution. The organicphase was separated out after settling had taken place and was thenwashed with 200 cm³ of saturated aqueous sodium chloride solution. Theorganic phase was separated out after settling had taken place, driedover magnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) to give 6.2 g of a residue, which waspurified by flash chromatography on silica [eluent:dichloromethane/ethyl acetate (1/1 by volume)]. After concentrating thefractions containing the expected product, a solid was obtained, whichwas stirred in 60 cm³ of a pentane/ethyl ether mixture (1/1 by volume)and then filtered off and dried under reduced pressure (2.7 kPa) to give2.1 g of 16,17-dehydro-16-trifluoromethanesulphonyloxypristinamycinII_(B) in the form of a white solid that melted at about 140° C. withdecomposition.

[0209]¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.96 (d, J=6.5 Hz:3H);0.99 (d, J=6.5 Hz:3H); 1.08 (d, J=6.5 Hz:3H); from 1.70 to 2.05 (mt:4H);1.80 (s:3H); 2.17 (mt:1H); 2.76 (mt:1H); 3.13 (dd, J=15 and 5.5 Hz:1H);3.46 (mt:1H); 3.46 (mt:1H); 3.60 (dd, J=15 and 6.5 Hz:1H); 3.72 (mt:1H);3.96 (mt:1H); 4.38 (mt:1H); 4.73 (dd, J=10 and 2 Hz:1H); 4.80 (dd, J=8.5and 4 Hz:1H); 4.90 (mt:1H); 5.61 (broad d, J=9 Hz:1H); from 5.75 to 5.85(mt:1H); 5.78 (dd, J=16 and 1.5 Hz:1H); 6.05 (mt:1H); 6.09 (d, J=16.5Hz:1H); 6.52 (dd, J=16 and 5.5 Hz:1H); 6.56 (s:1H); 8.19 (s:1H).

EXAMPLE 2

[0210] (16R)-16-Cyano-16-deoxopristinamycin II_(B):

[0211] (16S)-16-Cyano-16-deoxopristinamycin II_(B):

[0212] A solution of 2.5 g of 16-cyano-16,17-deoxopristinamycin II_(B)in 375 cm³ of a buffer solution prepared before by degassing, underargon for 15 minutes, a solution of 21.7 g of tetraethylammoniumtetrafluoroborate, 26.2 g of tetraethylammonium acetate tetrahydrate and5.7 cm³ of acetic acid, was transferred under an argon atmosphere into a1000 cm³ electrolysis tank (potentiostat-galvanostat: 555A Amel;integrator:731 Amel; millivoltmeter:minisis 6000 Tacussel; workingelectrode:sheet of mercury of about 5 cm², contact by platinum wiredipping into the mercury via a side tube closed off by a sphericalground joint; reference electrode (Ag/AgCl):ECS; counterelectrode:platinum wire wound in a spiral dipping into the electrolyte,separated from the cathode compartment by a nonwoven Nafion 125 cationicmembrane; the membrane was placed at the end of a threaded tube andattached by a threaded Teflon stopper, a Teflon seal ensuresleaktightness; modified glass metrohm cell (working volume ranging from10 cm³ to 60 cm³ depending on the test) and degassed under argon for 15minutes. A potential difference of −1.5 V (I=250 mA) was applied for 3hours (consumption=906 coulombs). The reaction mixture was removed fromthe electrolysis tank and then concentrated to dryness under reducedpressure (2.7 kPa). The residue, to which was added another residueobtained from an identical test using 2 g of16-cyano-16,17-dehydro-16-deoxopristinamycin II_(B), was taken up in 500cm³ of ethyl acetate. This organic phase was successively washed with200 cm³ of pH7 buffer solution, 150 cm³ of water, 100 cm³ of pH7 buffersolution and then dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa) and gave 4.25 gof an orange-yellow solid, to which were added 2.6 g of a yellow solidobtained from an identical test (using 2.79 9 of16-cyano-16,17-dehydro-16-deoxopristinamycin II_(B)). After purificationby flash chromatography on silica[eluent:dichloromethane/acetonitrile/methanol (92/4/4 by volume)] andconcentrating the fractions containing the expected products, 2 solidswere obtained, which were stirred in 10 cm³ of diethyl ether and thenfiltered off and dried under reduced pressure to give, respectively,0.73 g of the A isomer of 16-cyano-16-deoxopristinamycin II_(B), in theform of a pale yellow powder that melted at about 130° C. (dec.) and0.725 g of the B isomer of 16-cyano-16-deoxopristinamycin II_(B), in theform of a yellow powder that melted at about 130° C. with decomposition.

[0213] A isomer: ¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm). 0.96 (d,J=6.5 Hz:3H); 0.99 (d, J=6.5 Hz:3H); 1.09 (d, J=6.5 Hz:3H); from 1.70 to2.05 (mt:5H); 1.82 (s:3H); 2.13 (mt:1H); 2.22 (d, J=3.5 Hz:1H); 2.43(ddd, J=16−10 and 4 Hz:1H); 2.75 (mt:1H); 3.08 (dd, J=16 and 5 Hz:1H);3.21 (dd, J=16 and 6 Hz:1H); 3.30 (mt:1H); 3.49 (ddd, J=15−10 and 4Hz:1H); 3.92 (mt:2H); 4.36 (ddd, J=15−8 and 4 Hz:1H); from 4.70 to 4.85(mt:2H); 4.96 (mt:1H); 5.55 (broad d, J=9 Hz:1H); 5.68 (ddd, J=16−10 and4 Hz:1H); 5.78 (dd, J=16 and 1.5 Hz:1H); 5.94 (broad dd, J=8 and 4Hz:1H); 6.19 broad d, J=16 Hz:1H); 6.54 (dd, J=16 and 5 Hz:1H); 8.14(s:1H).

[0214] B isomer: ¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm). 0.96 (d,J=6.5 Hz:3H); 1.01 (d, J=6.5 Hz:3H); 1.10 (d, J=6.5 Hz:3H); 1.61 (ddd,J=15−10 and 4 Hz:1H); from 1.75 to 2.05 (mt:4H); 1.91 (s:3H); 2.09 (d,J=4 Hz:1H); from 2.05 to 2.30 (mt:2H); 2.77 (mt:1H); 2.92 (dd, J=16 and5.5 Hz:1H); from 3.20 to 3.35 (mt:2H); 3.49 (mt:1H); 3.86 (mt:1H); 4.10(mt:1H); 4.56 (mt:1H); from 4.75 to 4.90 (mt:1H); 4.79 (dd, J=10 and 1.5Hz:1H); 4.84 (dd, J=9 and 4 Hz; 1H); 5.36 (broad d, J=9 Hz:1H); 5.77(ddd, J=16−8.5 and 4 Hz:1H); 5.83 (dd, J=16 and 1.5 Hz:1H); 6.02 (broaddd, J=9 and 3 Hz:1H); 6.21 (large d, J=16 Hz:1H); 6.53 (dd, J=16 and 5Hz:1H); 8.16 (s:1H).

[0215] 16-cyano-16,17-dehydro-16-deoxopristinamycin II_(B) was preparedin the following way:

[0216] A solution of 2.3 g of16,17-dehydro-16-trifluoromethanesulphonyl-oxypristinamycin II_(B)(prepared as described in Example 1), 0.36 g of potassium cyanide, 0.16g of tetrakis(triphenylphosphine)palladium and 0.53 g of copper iodidein 25 cm³ of acetonitrile were refluxed under an argon atmosphere. Afterstirring for 4 hours, the reaction mixture was filtered through Celite®and the filtrate was concentrated to dryness under reduced pressure (2.7kPa). The residue was taken up in 50 cm³ of dichloromethane and washedtwice with 40 cm³ of water. The organic phase was dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) to give 2 g of an ochre-colored foam, which waspurified by two successive flash chromatographies on silica [eluent:dichloromethane/acetonitrile/methanol (96/2/2 by volume) and then adichloromethane/acetonitrile/methanol gradient (100/0/0 to 96/2/2 byvolume)]. After concentrating the fractions containing the expectedproduct, a solid was obtained, which was stirred in 10 cm³ of diethylether and then filtered off and dried under reduced pressure (2.7 kPa)to give 0.19 g of 16-cyano-16,17-dehydro-16-deoxopristinamycin II_(B) inthe form of a pale yellow solid that melted at about 142° C. withdecomposition.

[0217]¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm):0.96 (d, J=6.5 Hz:3H);1.00 (d, J=6.5 Hz:3H); 1.08 (d, J=6.5 Hz:3H); from 1.70 to 2.05 (mt:4H);1.78 (d, J=5 Hz:1H); 1.82 (s:3H); 2.16 (mt:1H); 2.78 (mt:1H); 3.03 (dd,J=14 and 5 Hz:1H); from 3.40 to 3.50 (mt:1H); 3.50 (dd, J=14 and 6.5Hz:1H); 3.72 (mt:1H); 3.96 (mt:1H); 4.36 (ddd, J=16−9 and 4 Hz:1H); 4.72(dd, J=10 and 2 Hz:1H); 4.80 (dd, J=9 and 4.5 Hz:1H); 4.91 (mt:1H); 5.58(broad d, J=9 Hz:1H); 5.77 (dd, J=16 and 1.5 Hz:1H); 5.79 (ddd, J=16−9and 4 Hz:1H); 6.00 (broad dd, J=9 and 5 Hz:1H); 6.10 (broad d, J=16Hz:1H); 6.51 (dd, J=16 and 5 Hz:1H); 7.08 (s:1H); 8.26 (s:1H).

[0218] The present invention also relates to pharmaceutical compositionscontaining at least one streptogramin group A derivative according tothe invention, in pure form, combined with at least one group Bstreptogramin derivative, where appropriate in the form of a salt,and/or in the form of a combination with at least one compatible andpharmaceutically acceptable diluent or adjuvant.

[0219] The compositions according to the invention may be used orally,parenterally, topically, rectally or as aerosols.

[0220] Solid compositions for oral administration which may be usedinclude, for example, tablets, pills, gel capsules, powders andgranules. In these compositions, the active product according to theinvention, generally in the form of a combination, can be mixed with atleast one inert diluent or adjuvant, such as sucrose, lactose, orstarch. These compositions may comprise substances other than diluents,for example, a lubricant such as magnesium stearate or a coatingintended for controlled release.

[0221] Liquid compositions for oral administration which may be usedinclude, for example, pharmaceutically acceptable solutions,suspensions, emulsions, syrups, and elixirs containing inert diluentssuch as water or liquid paraffin. These compositions may also comprisesubstances other than diluents, such as, for example, wetting,sweetening, or flavoring products.

[0222] The compositions for parenteral administration may be, forexample, sterile solutions or emulsions. Solvents or vehicles which maybe used include, for example, propylene glycol, polyethylene glycol,plant oils, such as, for example, olive oil, and injectable organicesters, for example, ethyl oleate. These compositions may also compriseat least one adjuvant, such as, for example, adjuvants chosen fromwetting agents, isotonic agents, emulsifiers, dispersants, andstabilizers.

[0223] The sterilization may be carried out in several ways, for exampleusing a bacteriological filter, by irradiation or by heating. Thecompositions may also be prepared in the form of sterile solidcompositions which may be dissolved at the time of use in sterile wateror any other injectable sterile medium.

[0224] The compositions for topical administration may be, for example,creams, ointments, lotions or aerosols.

[0225] The compositions for rectal administration may be, for example,suppositories or rectal capsules which contain, besides the activeprinciple, excipients such as cocoa butter, semisynthetic glycerides orpolyethylene glycols.

[0226] The compositions may also be aerosols. For use in the form ofliquid aerosols, the compositions may be stable sterile solutions orsolid compositions dissolved at the time of use in apyrogenic sterilewater, in saline or any other pharmaceutically acceptable vehicle. Foruse in the form of dry aerosols for direct inhalation, the activeprinciple can be finely divided and combined with a solid water-solublediluent or vehicle with a particle size ranging from, for example, 30 to80 μm, for example, dextran, mannitol or lactose.

[0227] In human therapy, for example, the novel streptograminderivatives according to the invention can be used for treatinginfections of bacterial origin. The doses depend on the desired effectand the duration of the treatment. The doctor will determine the dosage(s)he considers to be most suitable depending on the treatment, as afunction of the age, weight, degree of infection and the other factorsspecific to the individual to be treated. Generally, for example, thedoses can range from 0.5 to 3 g of active product in 2 or 3administrations per day, via the oral or parenteral route for an adult.

[0228] The example which follows illustrates a composition according tothe invention, without however exhibiting a limiting character.

EXAMPLE A

[0229] Tablets containing a 250 mg dose of active product and having thecomposition below can be prepared according to known, art-recognizedtechniques: (16R)-16-cyano-16-deoxopristinamycin II_(B) 175 mgPristinamycin I_(B) 75 mg Excipient: starch, hydrated silica, 500 mgdextrin, gelatin, magnesium stearate: qs

EXAMPLE B

[0230] Tablets containing a 250 mg dose of active product and having thecomposition below can be prepared according to known, art-recognizedtechniques: (16S)- 16-cyano-16-deoxopristinamycin II_(B) 175 mgPristinamycin ′B 75 mg Excipient: starch, hydrated silica, 500 mgdextrin, gelatin, magnesium stearate: qs

What is claimed is:
 1. A group A streptogramin derivative of formula (I)or a salt thereof:

wherein: R₁ is chosen from cyano and ethynyl groups, R₂ is chosen from ahydrogen atom, a methyl group, and an ethyl group, and the bond

is a single bond (27R stereochemistry) or a double bond.
 2. A group Astreptogramin derivative of formula (I) or a salt thereof according toclaim 1, wherein: R₁ is chosen from a cyano group and an ethynyl group,R₂ is a methyl group, and the bond

is a single bond (27R stereochemistry) or a double bond.
 3. A processfor preparing a group A streptogramin derivative of formula (I) or asalt thereof according to claim 1, said process comprising: reacting a16-sulphonyloxy derivative of formula (II):

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, R₃ is a perfluoroalkyl group comprising from 1 to 10 carbonatoms, and the bond

is a single bond (27R stereochemistry) or a double bond, with an alkalimetal cyanide, reducing the compound obtained from said reaction, andoptionally separating the 16R and 16S isomers obtained from saidreduction.
 4. A process for preparing a group A streptogramin derivativeof formula (I) or a salt thereof according to claim 1, said processcomprising: carbonylating a 16-sulphonyloxy derivative of formula (II):

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, R₃ is a perfluoroalkyl group comprising from 1 to 10 carbonatoms, and the bond

is a single bond (27R stereochemistry) or a double bond, to form alactone of formula (III):

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and the bond

is asi ngle bond (27R stereochemistry) or a double bond, reducing saidlactone to a lactol, reacting said lactol with dimethyldiazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate, andoptionally separating the 16R and 16S isomers obtained.
 5. A processaccording to claim 4, wherein said R₃ group is chosen from atrifluoromethyl group and a nonafluorobutyl group.
 6. A group Astreptogramin derivative of formula (II) or a salt thereof:

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, R₃ is a perfluoroalkyl group comprising from 1 to 10 carbonatoms, and the bond

is a single bond (27R stereochemistry) or a double bond.
 7. A group Astreptogramin derivative of formula (II) or a salt thereof according toclaim 6, wherein said R₃ group is chosen from a trifluoromethyl groupand a nonafluorobutyl group.
 8. A process for preparing a group Astreptogramin derivative of formula (II) or a salt thereof according toclaim 6, said process comprising: reacting a fluoride or an anhydride,wherein said fluoride or said anhydride comprises a perfluoroalkyl groupcomprising from 1 to 10 carbon atoms, with a streptogramin derivative offormula (IV):

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and the bond

is a single bond (27R stereochemistry) or a double bond, in the presenceof a base.
 9. A group A streptogramin derivative of formula (III) or asalt thereof:

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, and the bond

is a single bond (27R stereochemistry) or a double bond.
 10. A processfor preparing a group A streptogramin derivative of formula (III) or asalt thereof according to claim 9, said process comprising:carbonylating a 16-sulphonyloxy derivative of formula (II):

wherein: R₂ is chosen from a hydrogen atom, a methyl group, and an ethylgroup, R₃ is a perfluoroalkyl group comprising from 1 to 10 carbonatoms, and the bond

is a single bond (27R stereochemistry) or a double bond.
 11. Apharmaceutical composition comprising a pharmaceutically effectiveamount of at least one group A streptogramin derivative of formula (I)or salt thereof according to claim
 1. 12. A pharmaceutical compositionaccording to claim 11, further comprising at least one agent chosen frompharmaceutically acceptable diluents and pharmaceutically acceptableadjuvants.
 13. A pharmaceutical composition according to claim 11,further comprising at least one group B streptogramin derivative or saltthereof.
 14. A pharmaceutical composition according to claim 13, furthercomprising at least one agent chosen from pharmaceutically acceptablediluents and pharmaceutically acceptable adjuvants.
 15. A pharmaceuticalcomposition according to claim 13, wherein said at least one group Bstreptogramin derivative or salt thereof is chosen from natural group Bstreptogramin components.
 16. A pharmaceutical composition according toclaim 13, wherein said at least one group B streptogramin derivative orsalt thereof is chosen from pristinamycin IA, pristinamycin IB,pristinamycin IC, pristinamycin ID, pristinamycin IE, pristinamycin IF,pristinamycin IG, virginiamycin S1, virginiamycin S3, virginiamycin S4,vernamycin B, vernamycin C, and etamycin.
 17. A pharmaceuticalcomposition according to claim 13, wherein said at least one group Bstreptogramin derivative or salt thereof is chosen from semi-syntheticderivatives of formula (A) and salts thereof:

wherein: (1) Rb, Rc, Re, and Rf are each a hydrogen atom; Rd is chosenfrom a hydrogen atom and a dimethylamino group; and Ra is chosen from:(A) —CH₂R′a groups, wherein R′a is chosen from: (i) apyrrolidinyl-3-thio group, (ii) a piperidyl-3-thio group, (iii) apiperidyl-4-thio group, wherein said groups (i)-(iii) may beunsubstituted or substituted with at least one group chosen from alkylgroups, and (iv) alkylthio groups which are substituted with 1 or 2groups chosen from: (a) a hydroxysulfonyl group, (b) alkylamino groups,(c) dialkylamino groups, which may be unsubstituted or substituted withat least one group chosen from a mercapto group or dialkylamino groups,(d) a piperazine ring, a morpholino group, a thiomorpholino group, apiperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a3-pyrrolidinyl group, each of which may be unsubstituted or substitutedwith at least one group chosen from alkyl groups, and (B) ═CHR′a groups,wherein R′a is chosen from: (i) a pyrrolidinyl-3-amino group, (ii) apiperidyl-3-amino group and a piperidyl-4-amino group, (iii) apyrrolidinyl-3-oxy group, (iv) a piperidyl-3-oxy group and apiperidyl-4-oxy group, (v) a pyrrolidinyl-3-thio group, (vi) apiperidyl-3-thio group and a piperidyl-4-thio group, wherein said groups(i)-(vi) may be unsubstituted or substituted with at least one groupchosen from alkyl groups, (vii) alkylamino groups, (viii) alkyloxygroups, and (ix) alkylthio groups, wherein said groups (vii), (viii),and (ix) are substituted with 1 or 2 groups chosen from: (a) ahydroxysulfonyl group, (b) alkylamino groups, (c) dialkylamino groupsunsubstituted or substituted with at least one group chosen fromdialkylamino groups, (d) trialkylammonio groups, (e) a 4-imidazolylgroup, and a 5-imidazolyl group, each of which may be unsubstituted orsubstituted with at least one group chosen from alkyl groups, (f) apiperazine ring, a morpholino group, a thiomorpholino group, apiperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a3-pyrrolidinyl group, each of which may be unsubstituted or substitutedwith at least one group chosen from alkyl groups, (C) aquinuclidinyl-3-thiomethyl group, and (D) a quinuclidinyl-4-thiomethylgroup; or (2) Ra is a hydrogen atom, and (a) Rb, Re, and Rf are each ahydrogen atom, and Rd is chosen from a —NHCH₃ group and a —N(CH₃)₂group, and Rc is chosen from a chlorine atom and a bromine atom, or whenRd is a —N(CH₃)₂ group, Rc is chosen from (C₃-C₅) alkenyl groups, or (b)Rb, Rd, Re, and Rf are each a hydrogen atom, and Rc is chosen fromhalogen atoms, aminomonoalkyl groups, aminodialkyl groups, alkyloxygroups, a trifluoromethyloxy group, thioalkyl groups, (C₁-C₃) alkylgroups, and trihalomethyl groups, or (c) Rb, Rc, Re, and Rf are each ahydrogen atom, and Rd is chosen from halogen atoms, an ethylamino group,a diethylamino group, a methylethylamino group, alkyloxy groups, atrifluoromethyloxy group, thioalkyl groups, (C₁-C₆) alkyl groups, arylgroups, and trihalomethyl groups, or (d) Rb, Re, and Rf are each ahydrogen atom, Rc is chosen from halogen atoms, aminomonoalkyl groups,aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group,thioalkyl groups, and (C₁-C₃) alkyl groups, and Rd is chosen fromhalogen atoms, an amino group, aminomonoalkyl groups, aminodialkylgroups, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups,(C₁-C₆) alkyl groups, and trihalomethyl groups, or (e) Rc, Re, and Rfare each a hydrogen atom, and Rb and Rd are each a methyl group.
 18. Apharmaceutical composition according to claim 13, wherein said at leastone group B streptogramin derivative or salt thereof is chosen fromsemisynthetic derivatives of formula (B) and salts thereof:

wherein: (A) Y is chosen from (i) a nitrogen atom and (ii) ═CR₃— groups,and (1) when Y is chosen from ═CR₃— groups, R₁ is chosen from (a₁) ahydrogen atom, C₁-C₈ alkyl groups, and C₂-C₈ alkenyl groups, (b₁) C₃-C₈cycloalkyl groups, and saturated and unsaturated 3- to 8-memberedheterocyclyl groups, (c₁) an unsubstituted phenyl group, (d₁) a phenylgroup substituted with at least one substituent chosen from halogenatoms, a hydroxyl group, alkyl groups, alkyloxy groups, alkylthiogroups, alkylsulphinyl groups, alkylsulphonyl groups, an amino group,alkylamino groups, and dialkylamino groups, and (e₁) groups —NR′R″,wherein: R′ and R″, which are identical or different, are each chosenfrom a hydrogen atom, and C₁-C₃ alkyl groups, or R′ and R″, form,together with the nitrogen atom to which they are attached, a 3- to8-membered heterocyclyl group, wherein one of said members, in additionto said nitrogen atom, may be a heteroatom chosen from an oxygen atom, asulphur atom, and a nitrogen atom, and wherein said heterocyclyl groupis unsubstituted or substituted with a group chosen from alkyl groups,C₂-C₈ alkenyl groups, C₃-C₆ cycloalkyl groups, saturated and unsaturated4- to 6-membered heterocyclyl groups, a benzyl group, an unsubstitutedphenyl group, and a substituted phenyl group, as defined above in (d₁),(f₁) halomethyl groups, a hydroxymethyl group, and alkyloxymethylgroups, (g₁) alkylthiomethyl groups, wherein said alkyl portion isunsubstituted or substituted with an —NR′R″ group, and wherein said R′and said R″ are as defined above in (e₁), (h₁) alkylsulphinylmethylgroups, alkylsulphonylmethyl groups, an acyloxymethyl group, abenzoyloxymethyl group, a cyclopropylaminomethyl group, and—(CH₂)_(n)NR′R″ groups, wherein n is chosen from integers ranging from 1to 4, and wherein said R′ and said R″ are as defined above in (e₁), and(i_(i)) when R₃ is a hydrogen atom, R₁ is additionally chosen from aformyl group, a carboxyl group, alkyloxycarbonyl groups, and —CONR′R″groups, wherein said R′ and said R″ are defined as above in (e₁), and(2) when Y is a nitrogen atom, R₁ is chosen from (a₂) options (a₁),(b₁), (c₁), (d₁), and (e₁) as defined above, and (b₂) XR^(o) groups,wherein X is chosen from an oxygen atom, a sulphur atom, a sulphinylgroup, a sulphonyl group, and an —NH— group, and wherein R^(o) is chosenfrom (i) (C₁ to C₈) alkyl groups, (ii) (C₃ to C₆) cycloalkyl groups,(iii) saturated and unsaturated 3- to 8-membered heterocyclyl groups,(iv) 3- to 8-membered heterocyclylmethyl groups in which theheterocyclyl portion is attached to the methyl group by a carbon atom,(v) an unsubstituted phenyl group, (vi) phenyl groups substituted withat least one group chosen from halogen atoms, a hydroxyl group, alkylgroups, alkyloxy groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, an amino group, alkylamino groups, anddialkylamino groups, (vii) —(CH₂)_(n)NR′R″ groups, wherein R′ and R″ areas defined above in (e₁), and wherein n is chosen from integers rangingfrom 2 to 4, and (viii) if X is an NH group, R^(o) may also be ahydrogen atom; (B) R₂ is chosen from a hydrogen atom and C₁-C₃ alkylgroups, (C) R₃ is chosen from a hydrogen atom, alkyl groups, a carboxylgroup, alkyloxycarbonyl groups, and carbamoyl groups of formula—CO—NR′R″, wherein said R′ and said R″ are defined as above in (e₁), (D)Ra is chosen from a methyl group and an ethyl group, and (E) Rb, Rc, andRd are defined as follows: (1) Rb and Rc are each a hydrogen, atom andRd is chosen from a hydrogen atom, a methylamino group, and adimethylamino group, or (2) Rb is a hydrogen atom, Rc is chosen from ahydrogen atom, a chlorine atom, a bromine atom, and C₃-C₅ alkenylgroups, and Rd is chosen from —N(CH₃)R′″ groups, wherein R′″ is chosenfrom (a) alkyl groups, (b) C₂-C₄ hydroxyalkyl groups, (c) C₂-C₈ alkenylgroups, wherein said C₂-C₈ alkenyl groups are unsubstituted orsubstituted with (i) an unsubstituted phenyl group, (ii) acycloalkyl(C₃-C₆)methyl group, (iii) an unsubstituted benzyl group, (iv)a benzyl group substituted with at least one substituent chosen fromhalogen atoms, a hydroxyl group, alkyl groups, alkyloxy groups,alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, an aminogroup, alkylamino groups, and dialkylamino groups, or (v)heterocyclylmethyl groups and heterocyclylethyl groups, wherein saidheterocyclyl portions of said heterocyclylmethyl groups and saidheterocyclylethyl groups are chosen from saturated and unsaturated 5- to6-membered heterocyclyl groups comprising from 1 to 2 heteroatoms chosenfrom a sulphur atom, an oxygen atom, and a nitrogen atom, and whereinsaid heterocyclyl groups may be unsubstituted or substituted with agroup chosen from alkyl groups, C₂-C₈ alkenyl groups, C₃-C₆ cycloalkylgroups, saturated and unsaturated 4- to 6-membered heterocyclyl groups,an unsubstituted phenyl group, a benzyl group, or a substituted phenylgroup as defined above in (d₁), (d) a cyanomethyl group, (e) CH₂CORegroups, wherein Re is chosen from (i) —OR′e groups, wherein R′e ischosen from a hydrogen atom, C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, abenzyl group, and heterocyclylmethyl groups, wherein said heterocyclylportion is chosen from 5- to 6-membered heterocyclyl groups comprisingfrom 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, anda nitrogen atom, (ii) alkylamino groups, alkylmethylamino groups,heterocyclylamino groups and heterocyclylmethylamino groups, whereinsaid heterocyclyl portion of said heterocyclylamino groups and saidheterocyclylmethylamino groups is chosen from 5- to 6-membered saturatedheterocyclyl groups comprising from 1 to 2 heteroatoms chosen from asulphur atom, an oxygen atom, and a nitrogen atom, and wherein saidheterocyclyl groups may be unsubstituted or substituted with a groupchosen from alkyl groups, a benzyl group, and alkyloxycarbonyl groups,or (3) Rb is a hydrogen atom, Rd is chosen from an —NHCH₃ group and an—N(CH₃)₂ group, and Rc is chosen from a chlorine atom, and a bromineatom, and when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenylgroups, or (4) Rb and Rd are each a hydrogen atom, and Rc is chosen fromhalogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups,a trifluoromethoxy group, thioalkyl groups, C₁-C₆ alkyl groups, andtrihalomethyl groups, or (5) Rb and Rc are each a hydrogen atom, and Rdis chosen from halogen atoms, an ethylamino group, a diethylamino group,a methylethylamino group, alkyloxy groups, a trifluoromethoxy group,alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, C₁-C₆alkyl groups, a phenyl group, and trihalomethyl groups, or (6) Rb is ahydrogen atom, and Rc is chosen from halogen atoms, alkylamino groups,dialkylamino groups, alkyloxy groups, a trifluoromethoxy group,thioalkyl groups, and C₁-C₃ alkyl groups, and Rd is chosen from halogenatoms, an amino group, alkylamino groups, dialkylamino groups, alkyloxygroups, a trifluoromethoxy group, thioalkyl groups, C₁-C₆ alkyl groups,and trihalomethyl groups, or (7) Rc is a hydrogen atom, and Rb and Rdare each a methyl group.
 19. A pharmaceutical composition according toclaim 13, wherein said at least one group B streptogramin derivative orsalt thereof is chosen from semisynthetic derivatives of formula (C) andsalts thereof:

wherein: (A) R is chosen from (1) —NR₁R₂ groups, wherein R₁ and R₂,which may be identical or different, are each chosen from (₁) a hydrogenatom, (ii) (C₁-C₈) alkyl groups, (iii) (C₁-C₈) alkyl groups substitutedwith a hydroxyl group, (iv) (C₃-C₈) alkenyl groups, (v) (C₃-C₈)cycloalkyl groups, (vi) (C₁-C₈) alkyloxy groups, (vii) dialkylaminogroups, (viii) phenylalkyl groups, (ix) phenylalkyl groups substitutedwith at least one group chosen from halogen atoms, alkyl groups,hydroxyalkyl groups, alkyloxy groups, and dialkylamino groups, and (x)3- to 8-membered saturated and unsaturated heterocyclylalkyl groupscomprising at least one hetero atom chosen from nitrogen, oxygen, andsulphur, or (xi) R₁ and R₂ form, together with the nitrogen atom towhich they are attached, a saturated, partially saturated or unsaturatedmono- or polycyclic 3- to 12-membered heterocycle group, wherein one ofsaid members, in addition to said nitrogen atom, may be an atom chosenfrom oxygen, sulphur, and nitrogen, and wherein said heterocyclyl groupis unsubstituted or substituted with at least one group chosen from ahydroxyl group, alkyl groups, an unsubstituted phenyl group, a phenylgroup substituted with a halogen atom, phenylalkyl groups,phenyl(C₂-C₄)alkenyl groups, hydroxyalkyl groups, acyl groups,alkyloxycarbonyl groups, heterocyclyl groups and heterocyclylcarbonylgroups, wherein the heterocyclyl portion is 4- to 6-membered andsaturated or unsaturated and comprises at least one hetero atom chosenfrom nitrogen, sulphur, and oxygen, and (2) —SR₃ groups, wherein R₃ ischosen from (i) (C₁-C₈) alkyl groups and(C₃-C₈) cycloalkyl groupssubstituted with —NR₁R₂, wherein R₁ and R₂, which may be identical ordifferent, are each chosen from a hydrogen atom and alkyl groups, orform, together with the nitrogen atom to which they are attached, aheterocycle as defined above in (xi), and (ii) 3- to 7-memberedsaturated and unsaturated heterocyclyl and heterocyclylmethyl groups,wherein one of said members, in addition to said nitrogen atom, may bean atom chosen from oxygen, sulphur, and nitrogen, and wherein saidheterocyclyl portion is unsubstituted or substituted with an alkylgroup, (B)

is a residue of an unsaturated ring which is not substituted in the 5γposition

or the residue of a saturated ring which is substituted in the 5γposition with a fluorine atom

(C) Ra is chosen from a methyl group and an ethyl group, and (D) Rb, Rcand Rd are defined below: 1) Rb and Rc are each a hydrogen atom, and Rdis chosen from a hydrogen atom, a methylamino group, and a dimethylaminogroup, or 2) Rb is a hydrogen atom, Rc is chosen from a hydrogen atom, achlorine atom, a bromine atom, and a (C₃ to C₅) alkenyl group, and Rd is—N(CH₃)—R′″, wherein R′″ is chosen from: (1) alkyl groups, (2) (C₂ toC₄) hydroxyalkyl groups, (3) (C₂ to C₈) alkenyl groups, (4)phenylalkenyl groups, (5) cycloalkyl(C₃ to C₆)methyl groups, (6) anunsubstituted benzyl group, (7) a substituted benzyl group, (8)heterocyclylmethyl groups and heterocyclylethyl groups, (9) a —CH₂CNgroup, (10) a —CH₂COOH group, and (11) —CORe groups and —CH₂CORe groupsfor which either: (a) Re is —OR′e, wherein R′e is chosen from a hydrogenatom, C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, a benzyl group, andheterocyclylmethyl groups, wherein said heterocyclyl portion is chosenfrom 5- to 6-membered heterocyclyl groups comprising from 1 to 2heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogenatom, or (b) Re is chosen from alkylamino groups, alkylmethylaminogroups, heterocyclylamino groups, and heterocyclylmethylamino groups, or3) Rb is a hydrogen atom, Rd is chosen from an —NHCH₃ group and an—N(CH₃)₂ group, and Rc is chosen from a chlorine atom, and a bromineatom, and when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenylgroups, or 4) Rb and Rd are each a hydrogen atom, and Rc is chosen fromhalogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups,a trifluoromethoxy group, thioalkyl groups, (C₁-C₆) alkyl groups, andtrihalomethyl groups, or 5) Rb and Rc are each a hydrogen atom, and Rdis chosen from halogen atoms, an ethylamino group, a diethylamino group,a methylethylamino group, alkyloxy groups, a trifluoromethoxy group,alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, (C₁-C₆)alkyl groups, a phenyl group, and trihalomethyl groups, or 6) Rb is ahydrogen atom, Rc is chosen from halogen atoms, alkylamino groups,dialkylamino groups, alkyloxy groups, a trifluoromethoxy group,thioalkyl groups, (C₁-C₃) alkyl groups, and Rd is chosen from halogenatoms, an amino group, alkylamino groups, dialkylamino groups, alkyloxygroups, a trifluoromethoxy group, thioalkyl groups, (C₁-C₆) alkylgroups, and trihalomethyl groups, or 7) Rc is a hydrogen atom, and Rband Rd are each a methyl group.